Multicomponent cascade reactions: A novel and expedient approach to functionalized indoles by an unprecedented nucleophilic addition- heterocyclization-oxidative alkoxycarbonylation sequence

Article abstract of DOI:10.1002/adsc.201000642

A novel multicomponent cascade process is reported, based on the sequential combination between an initial nucleophilic attack step to an imine moiety and a palladium-catalyzed oxidative heterocyclization-alkoxycarbonylation process. By this new process, five simple molecules [2-alkynylaniline imines, alcohol (ROH), carbon monoxide (CO), alcohol (ROH), and oxygen (O₂)] are sequentially activated, selectively leading to high value-added functionalized indole derivatives in a single operation. Copyright

Full text of DOI:10.1002/adsc.201000642

FULL PAPERS
DOI: 10.1002/adsc.201000642
Multicomponent Cascade Reactions: A Novel and Expedient
Approach to Functionalized Indoles by an Unprecedented
Nucleophilic Addition-Heterocyclization-Oxidative
Alkoxycarbonylation Sequence
Bartolo Gabriele,a,* Lucia Veltri,b Giuseppe Salerno,b Raffaella Mancuso,b
and Mirco Costac
a
Dipartimento di Scienze Farmaceutiche, Universitꢀ della Calabria, 87036 Arcavacata di Rende (CS), Italy
Fax : (+39)-0984-492-044; phone: (+39)-0984-492813; e-mail: b.gabriele@unical.it
Dipartimento di Chimica, Universitꢀ della Calabria, 87036 Arcavacata di Rende (CS), Italy
Dipartimento di Chimica Organica e Industriale, Universitꢀ di Parma, 43100 Parma, Italy
b
c
Received: August 16, 2010; Published online: December 8, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000642.
Abstract: A novel multicomponent cascade process cohol (ROH), and oxygen (O2)] are sequentially acti-
is reported, based on the sequential combination be- vated, selectively leading to high value-added func-
tween an initial nucleophilic attack step to an imine tionalized indole derivatives in a single operation.
moiety and a palladium-catalyzed oxidative hetero-
cyclization-alkoxycarbonylation process. By this new
process, five simple molecules [2-alkynylaniline Keywords: carbonylation; cascade reactions; cycliza-
imines, alcohol (ROH), carbon monoxide (CO), al- tion; indoles; palladium
Introduction
In this work, we report a novel multicomponent
cascade process, which allows a convenient direct syn-
Cascade reactions have recently acquired an increas- thesis of functionalized indoles through an unprece-
ing importance in synthesis, owing to the possibility to dented sequence of steps, involving ROH addition to
obtain the target molecule through the concatenation the imino group of 2-alkynylaniline imines to give
of different steps, occurring in situ in ordered se- [(alkoxymethyl)(2-alkynylaryl)]amines as intermedi-
quence.[1] Of particular interest are multicomponent ates, followed by the PdI2-catalyzed reaction of the
cascade reactions, in which the final product is ob- latter with CO, ROH, and O2 to give the final prod-
tained by the sequential assembly of several simple ucts [1-(alkoxyarylmethyl)indole-3-carboxylic esters,
building blocks. This approach, in fact, permits one to Scheme 2]. Thus, five simple molecules (2-alkynylani-
construct multifunctionalized, high value-added com- line imines, ROH, CO, ROH, and O2) are sequential-
pounds in a single operation through the concatena- ly activated in a 2-step cascade process, selectively
tion of several steps, each one employing readily leading to highly substituted, functionalized indole de-
available starting materials, as shown in Scheme 1 in rivatives in a single operation.
the case of 2 steps.
Results and Discussion
We began our investigations with benzylidene-(2-phe-
nylethynyl)phenylamine 3aa (R1 =R4 =Ph, R2 =R3 =
H), obtained from the reaction between 2-(phenyl-
AHCTUNGTREGeNNUN thynyl)aniline 1a with benzaldehyde 2a in the pres-
ence of molecular sieves 4 ꢁ. Owing to the sensitivity
of the imino group to hydrolysis, 3aa was used the
Scheme 1. A schematic representation of a 2-step multicom-
ponent cascade reaction. A, B,…F are the reactants; I is the
intermediate product ensuing from the first step; P is the
final product.
Adv. Synth. Catal. 2010, 352, 3355 – 3363
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Bartolo Gabriele et al.
FULL PAPERS
unidentified heavy products [Eq. (1) and Table 1,
entry 1].
In order to hinder this substrate hydrolysis, we then
carried out the reaction in the presence of a dehydrat-
Scheme 2. Multicomponent cascade reaction leading to 1-
(alkoxyarylmethyl)indole-3-carboxylic esters from 2-alkyn-
ACHTUNGTRENNUNG
ing agent, such as trimethyl orthoformate. To our de-
light, working under conditions similar to those given
above, but in a 1:1 mixture MeOH-HC
ACHTUNGRTENN(UNG OMe)3 as the
solvent, the reaction course changed completely, with
crude material without further purification, which formation of methyl 1-(methoxyphenylmethyl)-2-phe-
also simplified the synthetic procedure (see the Ex- nylindole-3-carboxylate 4aa in 51% HPLC yield (46%
perimental Section for details). Thus, crude 3aa was isolated) based on starting 1a (Table 1, entry 2). For-
initially allowed to react in MeOH (R=Me) at 808C mation of 4aa corresponded to a novel multicompo-
and under 20 atm of a 4:1 mixture of CO-air[2] for nent cascade process, involving MeOH addition to
15 h, in the presence of catalytic amounts of PdI2 the imino group of 3aa followed by PdI2-catalyzed ox-
(2 mol%) in conjunction with KI (20 mol%).[3] Under idative 5-endo-dig cyclization-alkoxycarbonylation
these conditions, however, the substrate underwent (Scheme 3).[4]
hydrolysis, and was converted into a mixture of 1a,
Having assessed the possibility to realize a direct
2a, and benzaldehyde dimethyl acetal, together with synthesis of indole-3-carboxylic ester derivative 4aa
Table 1. Reactions of benzylidene-(2-phenylethynyl)phenylamine 3aa with CO, MeOH, and O2 under different conditions.[a]
Entry KI:PdI2 molar ratio Solvent
T [8C] Substrate concentration[b] t [h] Yield [%][c] of 4aa
1[d]
2
3
4
5
10
10
10
10
5
50
10
10
10
10
10
MeOH
HC(OMe)3-MeOH, 1:1 v/v
MeC
HC(OMe)3-MeOH, 1:1 v/v
HC(OMe)3-MeOH, 1:1 v/v
HC(OMe)3-MeOH, 1:1 v/v
HC(OMe)3-MeOH, 2:1 v/v
HC(OMe)3-MeOH, 3:1 v/v
HC(OMe)3-MeOH, 4:1 v/v
(OMe)3-MeOH, 1:1 v/v
(OMe)3-MeOH, 1:1 v/v
80
80
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.05
15
15
15
4
15
15
15
15
15
15
15
–
N
51 (46)
35
45
47
51
55
58
45
61
(OMe)3-MeOH, 1:1 v/v 80
E
N
R
N
G
G
T
A
100
80
80
80
80
80
80
80
6
7
8
9
10[e]
11
HC
HC
60
[a]
Unless otherwise noted, all reactions were carried out using 2 mol% of PdI2 under 20 atm (at 258C) of a 4:1 mixture of
CO-air. Conversion of 3aa was practically quantitative in all cases (by HPLC).
Mmol of starting 1a per mL of solvent.
[b]
[c]
[d]
HPLC yield (isolated yield) based on starting 1a.[d]
The reaction led to the formation of 1a (35%), 2a (18%) and benzaldehyde dimethyl acetal (80%), together with uniden-
tified heavy products (chromatographically immobile materials).
The reaction was carried out under 40 atm (at 258C) of a 4:1 mixture of CO-air.
[e]
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Multicomponent Cascade Reactions: A Novel and Expedient Approach to Functionalized Indoles
Scheme 3. Proposed reaction mechanism for the formation of 1-(alkoxyarylmethyl)indole-3-carboxylic esters 4 from 2-alk-
ACHTUNGTRENNUNGynylaniline imines 3.
from 2-(phenylethynyl)aniline 3aa through a multi- 3-carboxylic ester derivatives being selectively formed
component cascade process, we then screened the re- in 52–73% isolated yields (based on starting 2-alk-
action conditions in order to improve the yield and
the selectivity toward the desired product, taking the
reaction of Table 1, entry 2, as the model reaction.
ACHTUNGTRENNyUNG nylaniline 1) with 2–5 mol% of catalyst.
The use of MeC
a significantly lower yield of 4aa (35%, entry 3). A
G
G
lower selectivity toward 4aa was also obtained when In conclusion, we have disclosed an unprecedented
working at 1008C rather than 808C (entry 4) or using multicomponent cascade reaction, consisting of ROH
a lower KI:PdI2 molar ratio (5 rather than 10, addition of the imino group of 2-alkynylaniline imines
entry 5), while with a large excess of KI the results 3 (obtained as crude products from the condensation
were practically unchanged with respect to those ob- between alkynylanilines 1 and benzaldehydes 2) fol-
tained with a KI:PdI2 molar ratio of 10 (entry 6). On lowed by PdI2-catalyzed oxidative 5-endo-dig cycliza-
the other hand, a higher yield of 4aa was obtained tion–alkoxycarbonylation. The possibility to assembly
when the reaction was carried out in 2:1 or 3:1 multifunctional indole derivatives, such as 1-(alkoxy-
HC
N
ACHTUNGTRENaNUGN rylmethyl)indole-3-carboxylic esters 4, starting from
tively), although the use of a 4:1 HCAHCUTNGTRENNUNG
mixture was detrimental (entry 9). A higher yield of lines, benzaldehydes, CO, ROH, and O2) is remark-
4aa was obtained by working under a total pressure able,[5–7] also in view of the importance of the indole
of 40 atm rather than 20 atm (entry 10) or with a heterocyclic core in general,[8] and of the indole-3-car-
lower substrate concentration (0.05 rather than boxylic ester motif in particular.[9,10]
0.1 mmol per mL of solvent, entry 11).
On the basis of these results, the next experiments
were carried out under the following optimized condi-
tions: 2 mol% of PdI2, KI:PdI2 molar ratio=10, T=
Experimental Section
808C, solvent: 3:1 HCACTHNUTRGNE(NUG OMe)3-MeOH, substrate con-
General Remarks
centration=0.05 mmol of substrate per mL of solvent,
total pressure=40 atm (4:1 CO-air). Under these con-
ditions, the product 4aa was obtained in 65% HPLC
yield based on starting 1a (60% isolated, Table 2,
entry 1). The reaction was then generalized to other
variously substituted 2-alkynylaniline imines 3, ob-
tained from different aryl aldehydes, and bearing
alkyl or aryl groups on the triple bond and electron-
withdrawing as well as p-donating groups on the aro-
matic ring. The results, shown in Table 2, confirm that
Solvents and chemicals were reagent grade and were used
without further purification. Substrates were prepared and
characterized as described in the Supporting Information.
All reactions were analyzed by TLC on silica gel 60 F254
HPLC or GLC. HPLC experiments were performed using a
Shimadzu LC-20AB HPLC system with Shimadzu
SPD20A detector and with a C-18 reverse phase silica
column (Supelco Discovery 4.6ꢃ150 mm, 5 mm). The wave-
length for UV detection was set at 254 nm and the dwell
time in the gamma detector was 1 s in a 10 mL loop. The elu-
,
a
the process is quite general, the corresponding indole- tion conditions were as follows: solvent A=H2O (1%
Adv. Synth. Catal. 2010, 352, 3355 – 3363
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Table 2. Synthesis of 1-(alkoxyarylmethyl)indole-3-carboxylic esters 4 from 2-alkynylaniline imines 3 by the multicomponent
cascade reaction.[a]
Entry
PdI2 [mol%]
1
R1
R2
R3
2
R4
4
R
Yield [%][b] of 4
1
2
3
4
5
6
7
8
2
2
5
2
2
5
2
5
5
2
2
5
2
2
2
5
2
5
2
5
2
1a
1b
1b
1c
1d
1d
1e
1e
1e
1f
1f
1f
1g
1h
1i
1i
1j
1j
1a
1a
1a
Ph
p-Br-C6H4
p-Br-C6H4
p-Me-C6H4
3-thienyl
3-thienyl
Bu
Bu
Bu
Ph
Ph
Ph
Bu
Bu
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Ph
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4aa
4ba
4ba
4ca
4da
4da
4ea
4ea
4ea’
4fa
4fa’
4fa’
4ga
4ha
4ia
4ia
4ja
4ja
4ab
4ab
4ac
Me
Me
Me
Me
Me
Me
Me
Me
Et
60
51
60
60
45
58
46
55
52
70
50
68
62
52
56
73
40
55
49
60
62
9
10
11
12
13
14
15
16
17
18
19
20
21
Me
Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CF3
CF3
H
Ph
Ph
Ph
Ph
Ph
Ph
p-Me-C6H4
p-Me-C6H4
p-Br-C6H4
H
H
[a]
Unless otherwise noted, all reactions were carried out at 808C in a 3:1 (v/v) mixture of HC(OR)3-ROH as the solvent
(0.05 mmol of starting 1 per mL of solvent), under 40 atm (at 258C) of a 4:1 mixture of CO-air for 15 h. Conversion of 3 was
practically quantitative in all cases (by HPLC).
[b]
Isolated yield based on starting 1.
AcOH), solvent B=CH3CN; 0–5 min 25% B; 5–35 min
25% B to 88% B; 35–37 min 88% B; 37–38 min 88% B to
25% B; 38–43 min 25% B. The flow rate was maintained at
1 mLminÀ1. The GLC analyses was performed using a capil-
lary column with polymethylsilicone +5% phenylsilicone as
the stationary phase (HP-5). Column chromatography was
performed on silica gel 60 (70–230 mesh). Evaporation
refers to the removal of solvent under reduced pressure.
Melting points are uncorrected. 1H NMR and 13C NMR
spectra were recorded at 258C on a Bruker DPX Avance
300 Spectrometer in CDCl3 solutions at 300 MHz and
75 MHz, respectively, with Me4Si as internal standard.
19F NMR spectra were recorded at 258C on a Bruker DPX
Avance 500 Spectrometer in CDCl3 solutions at 471 MHz
with CF2Br2 as internal standard. Chemical shifts (d) and
coupling constants (J) are given in ppm and in Hz, respec-
tively. IR spectra were taken with a JASCO FT-IR 4200
spectrometer. Mass spectra were obtained using a Shimadzu
QP-2010 GC-MS apparatus at 70 eV ionization voltage. Mi-
croanalyses were carried out with a Carlo Erba Elemental
Analyzed Mod. 1106.
General Procedure for the Catalytic Synthesis of 1-
(Alkoxyarylmethyl)indole-3-carboxylic Esters 4
1st Step: preparation of crude 2-alkynylaniline imines 3: A
mixture of aldehyde 2 (10 mmol) (benzaldehyde 2a: 1.06 g;
4-methylbenzaldehyde 2b: 1.20 g; 4-bromobenzaldehyde 2c:
1.85 g), 2-alkynylaniline 1 (6.67 mmol) [2-phenylethynylani-
line 1a: 1.289 g; 2-(4-bromophenylethynyl)aniline 1b:
1.815 g; 2-p-tolylethynylaniline 1c: 1.382 g; 2-thiophen-3-yle-
thynylaniline 1d: 1.329 g; 2-hex-1-ynylaniline 1e: 1.156 g; 4-
chloro-2-phenylethynylaniline 1f: 1.519 g; 2-hex-1-ynyl-4-
phenylaniline 1g: 1.663 g; 2-hex-1-ynyl-4-methylaniline 1h:
1.250 g; 5-methyl-2-phenylethynylaniline 1i: 1.382 g; 2-phe-
nylethynyl-5-trifluoromethylaniline 1j: 1.743 g] and molecu-
lar sieves 4ꢁ (2 g) in anhydrous CH2Cl2 (3 mL), was stirred
at room temperature for 16 h (1a–1i) or at 408C for 24 h
(1j). The mixture was filtered on celite and the solvent was
removed under vacuum. The crude imine thus obtained was
diluted with HC(OR)3 (R=Me or Et, 25 mL) and the solu-
tion used as such for the next step.
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Multicomponent Cascade Reactions: A Novel and Expedient Approach to Functionalized Indoles
2nd Step: catalytic oxidative carbonylation procedure
leading to 1-(alkoxyarylmethyl)indole-3-carboxylic esters
4: A 250-mL stainless steel autoclave was charged in the
presence of air with PdI2 (7.3 mg, 2.03ꢃ10À2 mmol, or
18.2 mg, 5.05ꢃ10À2 mmol, see Table 2), KI (33.5 mg,
0.20 mmol, or 84.0 mg, 0.51 mmol, see Table 2), 11.3 mL of
HC(OR)3 (R=Me or Et), anhydrous ROH (R=Me or Et,
5.1 mL), and 3.8 mL of the solution of the crude imine in
HC(OR)3 (R=Me or Et), prepared as described above (for-
mally deriving from 1.01 mmol of starting 1). The autoclave
was sealed and, while the mixture was stirred, the autoclave
was pressurized with CO (32 atm) and air (up to 40 atm).
After being stirred at 808C for 15 h, the autoclave was
cooled, degassed and opened. The solvent was evaporated,
and the products were purified by column chromatography
on silica gel using 95:5 hexane-AcOEt (for 4aa, 4ba, 4ea,
4fa, 4ga, 4ja, 4ab, and 4ac), 98:2 hexane-AcOEt (for 4ca,
4ha, and 4ia), 9:1 hexane-AcOEt (for 4da and 4fa’), or 99:1
hexane-AcOEt (for 4ea’).
(M+, 10), 249 (5), 204 (4), 193 (3), 122 (8), 121 (100), 105
(4), 91 (14), 77 (20); anal. calcd. for C25H23NO3 (385.46): C
77.90, H 6.01, N 3.63; found: C 77.80; H, 6.03, N 3.62.
1-(Methoxyphenylmethyl)-2-thiophen-3-ylindole-3-carbox-
ylic acid methyl ester (4da): Yield: 220.7 mg (58% based on
starting 1d; Table 2, entry 6); colorless solid; mp 179–1808C.
IR (KBr): n=1693 (s), 1575 (w), 1495 (m), 1444 (m), 1407
(m), 1335 (m), 1298 (w), 1239 (m), 1184 (m), 1151(m), 1088
(m), 957 (m), 789 (m), 755 (m), 730 (m) cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=8.24–8.19 (m, 1H, H-4), 7.46–7.42
(m, 2H, aromatic), 7.34–7.18 (m, 8H, aromatic), 7.11–7.04
(m, 1H, aromatic), 6.28 (s, 1H, CHOMe), 3.91 (s, 3H,
CO2Me), 3.28 (s, 3H, CHOCH3); 13C NMR (75 MHz,
CDCl3): d=165.5, 142.1, 138.0, 134.4, 130.8, 129.3, 128.5,
128.4, 127.2, 126.7, 125.8 (2 C), 123.0, 122.4, 121.7, 113.9,
106.8, 87.3, 55.9, 51.0; GC-MS: m/z=377 (M+, 10), 185 (3),
122 (9), 121 (100), 105 (5), 91 (12), 77 (17); anal. calcd. for
C22H19NO3S (377.46): C 70.00, H 5.07, N 3.71, S 8.50; found:
C 70.92; H, 5.06, N 3.72, S 8.46.
1-(Methoxyphenylmethyl)-2-phenylindole-3-carboxylic
acid methyl ester (4aa): Yield: 225.3 mg (60% based on
starting 1a; Table 2, entry 1); yellow solid; mp 110–1158C.
IR (KBr): n=1712 (s), 1546 (w), 1485 (w), 1454 (m), 1401
(m), 1335 (w), 1256 (m), 1190 (w), 1147 (s), 1085 (s), 1073
2-Butyl-1-(methoxyphenylmethyl)indole-3-carboxylic acid
methyl ester (4ea): Yield: 195.0 mg (55% based on starting
1e; Table 2, entry 8); yellow solid; mp 93–968C. IR (KBr):
n=1695 (s), 1528 (w), 1461 (m), 1437 (m), 1408 (m), 1335
(m), 1226 (m), 1136 (w), 1114 (m), 1023 (w), 781 (w), 758
1
1
(m), 707 (s) cmÀ1; H NMR (300 MHz, CDCl3): d=8.25–8.21
(m), 732 (m) cmÀ1; H NMR (300 MHz, CDCl3): d=8.15 (d,
(m, 1H, H-4), 7.57–7.36 (m, 5H, aromatic), 7.34–7.19 (m,
7H, aromatic), 7.11–7.04 (m, 1H, aromatic), 6.18 (s, 1H,
CHOMe), 3.78 (s, 3H, CO2Me), 3.25 (s, 3H, CHOCH3);
13C NMR (75 MHz, CDCl3): d=165.5, 147.4, 138.0, 134.2,
131.4, 129.3, 128.5, 128.4, 128.3, 127.2, 125.9, 123.0, 122.5,
121.8, 114.1, 106.3, 87.2, 56.0, 50.9; GC-MS: m/z=371 (M+,
8), 235 (3), 190 (5), 179 (3), 122 (8), 121 (100), 105 (4), 91
(12), 77 (17); anal. calcd. for C24H21NO3 (371.43): C 77.61, H
5.70, N 3.77; found: C 77.73; H, 5.68, N 3.76.
br, J=8.1 Hz, 1H, H-4), 7.33–7.15 (m, 7H, aromatic), 7.09–
7.01 (m, 1H, aromatic), 6.59 (s, 1H, CHOMe), 3.95 (s, 3H,
CO2Me), 3.43–3.30 (m, 1H, CHHCH2CH2CH3), 3.38 (s, 3H,
CHOCH3), 3.21–3.08 (m, 1H, CHHCH2CH2CH3), 1.68–1.35
(m, 4H, CH2CH2CH2CH3), 0.90 (t, J=7.3 Hz, 3H,
CH2CH2CH2CH3); 13C NMR (75 MHz, CDCl3): d=166.3,
150.2, 138.0, 135.1, 128.55, 128.51, 127.1, 125.8, 122.3, 122.0,
121.5, 112.7, 105.0, 86.4, 56.2, 50.8, 31.8, 25.7, 22.9, 13.7; GC-
MS: m/z=351 (M+, 12), 156 (5), 129 (4), 122 (13), 121 (100),
105 (5), 91 (17), 77 (19); anal. calcd. for C22H25NO3 (351.44):
C 75.19, H 7.17, N 3.99; found: C 75.22; H, 7.16, N 3.99.
2-Butyl-1-(ethoxyphenylmethyl) indole-3-carboxylic acid
ethyl ester (4ea’): Yield: 198.8 mg (52% based on starting
1e; Table 2, entry 9); yellow oil. IR (film): n=2958 (m),
2871 (m), 1695 (s), 1536 (m), 1459 (m), 1414 (m), 1379 (m),
1337 (m), 1287 (m), 1259 (m), 1219 (m), 1157 (m), 1109 (m),
2-(4-Bromophenyl)-1-(methoxyphenylmethyl)indole-3-car-
boxylic acid methyl ester (4ba): Yield: 273.0 mg (60% based
on starting 1b; Table 2, entry 3); colorless solid; mp 158–
1598C. IR (KBr): n=1697 (s), 1486 (w), 1438 (w), 1389 (m),
1343 (m), 1194 (m), 1161 (m), 1083 (s), 1009 (w), 764 (m),
700 (m) cmÀ1 1H NMR (300 MHz, CDCl3): d=8.25–8.20
;
(m, 1H, H-4), 7.68–7.52 (m, 2H, aromatic), 7.36–7.16 (m,
9H, aromatic), 7.14–7.05 (m, 1H, aromatic), 6.16 (s, 1H,
CHOMe), 3.80 (s, 3H, CO2Me), 3.25 (s, 3H, CHOCH3);
13C NMR (75 MHz, CDCl3): d=165.4, 145.8, 137.9, 134.6,
131.6, 130.4, 128.6, 127.2, 125.9, 123.8, 123.3, 122.6, 121.9,
114.1, 106.8, 87.5, 56.1, 50.9; GC-MS: m/z=451 [(M+2)+,
3], 449 (M+, 2), 249 (3), 190 (5), 178 (2), 122 (9), 121 (100),
105 (5), 91 (13), 78 (3), 77 (19); anal. calcd. for
C24H20BrNO3 (450.32): C 64.01, H 4.48, Br, 17.74, N 3.11;
found: C 64.15; H, 4.49, Br, 17.81, N 3.10.
1034 (m), 790 (m), 732 (m) cmÀ1 1H NMR (300 MHz,
;
CDCl3): d=8.19–8.14 (m, 1H, H-4), 7.34–7.16 (m, 7H, aro-
matic), 7.09–7.02 (m, 1H, aromatic), 6.69 (s, 1H, CHOEt),
4.42 (q, J=7.1 Hz, 2H, CO2CH2CH3), 3.70–3.57 (m, 1H,
CHOCHHCH3), 3.52–3.40 (m, 1H, CHOCHHCH3), 3.40–
3.27 (m, 1H, CHHCH2CH2CH3), 3.19–3.07 (m, 1H,
CHHCH2CH2CH3), 1.67–1.34 (m, 4H, CH2CH2CH2CH3),
1.47 (t, J=7.1 Hz, 3H, CO2CH2CH3), 1.26 (t, J=7.1 Hz, 3H,
CO2CH2CH3), 0.88 (t, J=7.1 Hz, 3H, CH2CH2CH2CH3);
13C NMR (75 MHz, CDCl3): d=165.8, 149.8, 138.6, 135.5,
128.54, 128.46, 127.4, 126.0, 122.3, 121.9, 121.6, 112.6, 106.1,
85.1, 64.4, 59.5, 31.9, 25.9, 23.0, 14.8, 14.7, 13.7; GC-MS:
m/z=379 (M+, 5), 334 (1), 217 (1), 174 (3), 156 (2), 136 (9),
135 (88), 108 (8), 107 (100), 91 (8), 79 (86), 77 (24); anal.
calcd. for C24H29NO3 (379.49): C 75.96, H 7.70, N 3.69;
found: C 75.90; H, 7.70, N 3.70.
1-(Methoxyphenylmethyl)-2-p-tolylindole-3-carboxylic
acid methyl ester (4ca): Yield: 233.9 mg (60% based on
starting 1c; Table 2, entry 4); colorless solid; mp 127–1298C.
IR (KBr): n=1688 (s), 1547 (w), 1496 (m), 1386 (m), 1332
(m), 1251 (m), 1189 (m), 1164 (m), 1119 (s), 1074 (m), 989
(m), 756 (m), 730 (m) cmÀ1 1H NMR (300 MHz, CDCl3):
;
d=8.23–8.19 (m, 1H, H-4), 7.34–7.19 (m, 11H, aromatic),
7.10–7.03 (m, 1H, aromatic), 6.20 (s, 1H, CHOMe), 3.80 (s,
3H, CO2Me), 3.24 (s, 3H, CHOCH3), 2.42 (s, 3H, Me);
13C NMR (75 MHz, CDCl3): d=165.6, 147.8, 139.2, 138.0,
134.2, 129.1, 128.5, 128.4, 128.2, 127.2, 125.9, 122.9, 122.4,
121.7, 114.1, 106.1, 87.1, 55.9, 50.9, 21.5; GC-MS: m/z=385
5-Chloro-1-(methoxyphenylmethyl)-2-phenylindole-3-car-
boxylic acid methyl ester (4fa): Yield: 286.0 mg (70% based
on starting 1f; Table 2, entry 10); yellow solid; mp 171–
1738C. IR (KBr): n=1708 (s), 1543 (w), 1455 (m), 1374 (m),
1340 (w), 1254 (m), 1189 (w), 1153 (m), 1133 (m), 1075 (m),
Adv. Synth. Catal. 2010, 352, 3355 – 3363
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Bartolo Gabriele et al.
FULL PAPERS
1028 (w), 971 (w), 873 (m), 807 (m), 715 (m) cmÀ1; H NMR
(300 MHz, CDCl3): d=8.21 (d, J=2.0 Hz, 1H, H-4), 7.56–
7.43 (m, 4H, aromatic), 7.37–7.28 (m, 4H, aromatic), 7.26–
7.18 (m, 2H, aromatic), 7.14 (distorted d, J=8.9 Hz, 1H, H-
7), 7.03 (distorted dd, J=8.9, 2.0 Hz, 1H, H-6) 6.15 (s, 1H,
CHOMe), 3.79 (s, 3H, CO2Me), 3.25 (s, 3H, CHOCH3);
13C NMR (75 MHz, CDCl3): d=165.0, 148.4, 137.7, 132.6,
131.5, 130.9, 129.7, 129.5, 128.64, 128.60, 128.5, 128.4, 125.8,
123.5, 121.4, 115.1, 106.0, 87.4, 56.0, 51.0; GC-MS: m/z=407
[(M+2)+, 2], 405 (M+, 4), 284 (1), 269 (4), 213 (2), 190 (5),
163 (2), 122 (9), 121 (100), 105 (4), 91 (13), 77 (19); anal.
calcd. for C24H20ClNO3 (405.87): C 71.02, H 4.97, N 3.45;
found: C 71.10; H, 4.96, N 3.46.
CHOCH3), 3.19–3.06 (m, 1H, CHHCH2CH2CH3), 2.43 (s,
br, 3H, CH3 at C-5), 1.69–1.33 (m, 4H, CH2CH2CH2CH3),
0.89 (t, J=7.3 Hz, CH2CH2CH2CH3); 13C NMR (75 MHz,
CDCl3): d=166.3, 150.1, 138.1, 133.4, 131.4, 129.0, 128.5,
127.4, 125.8, 123.8, 121.3, 112.3, 104.6, 86.4, 56.1, 50.7, 31.8,
25.7, 22.9, 21.5, 13.7; GC-MS: m/z=365 (M+, 9), 170 (2),
142 (2), 122 (9), 121 (100), 105 (3), 91 (11), 77 (13); anal.
calcd. for C23H27NO3 (365.47): C 75.59, H 7.45, N 3.83;
found: C 75.46; H, 7.44, N 3.84.
1
1-(Methoxyphenylmethyl)-6-methyl-2-phenylindole-3-car-
boxylic acid methyl ester (4ia): Yield: 282.5 mg (73% based
on starting 1i; Table 2, entry 16); yellow solid; mp 149–
1508C. IR (KBr): n=2949 (m), 1701 (s), 1604 (w), 1545 (m),
1483 (m), 1398 (m), 1337 (m), 1257 (m), 1231 (m), 1146 (m),
5-Chloro-1-(ethoxyphenylmethyl)-2-phenylindole-3-car-
boxylic acid ethyl ester (4fa’): Yield: 298.5 mg (68% based
on starting 1f; Table 2, entry 12); yellow solid; mp 159–
1618C. IR (KBr): n=2978 (m), 1689 (s), 1539 (w), 1450 (m),
1408 (m), 1342 (m), 1315 (m), 1238 (w), 1173 (s), 1080 (s),
1082 (m), 1027 (w), 817 (m), 759 (m) cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=8.10 (d, br, J=8.1 Hz, 1H, H-4),
7.55–7.37 (m, 5H, aromatic), 7.34–7.20 (m, 5H, aromatic),
7.08 (dd, J=8.1, 1.1 Hz, 1H, H-5), 7.04–7.01 (m, 1H, H-7),
6.15 (s, 1H, CHOMe), 3.76 (s, 3H, CO2Me), 3.25 (s, 3H,
CHOCH3), 2.30 (s, 3H, Me at C-6); 13C NMR (75 MHz,
CDCl3): d=165.6, 146.9, 138.0, 134.7, 132.8, 131.5, 130.3
(br), 129.1, 128.5, 128.4, 128.3, 125.9, 125.1, 124.3, 121.4,
113.9, 106.2, 87.2, 56.0, 50.8, 21.8; GC-MS: m/z=385 (M+,
17), 354 (1), 294 (1), 264 (1), 249 (2), 232 (1), 204 (1), 193
(2), 178 (1), 122 (10), 121 (100), 105 (4), 91 (10), 77 (17);
anal. calcd. for C25H23NO3 (385.46): C 77.90, H 6.01, N 3.63;
found: C 77.98; H, 6.03, N 3.62.
1030 (m), 887 (m), 786 (m), 713 (m) cmÀ1
;
1H NMR
(300 MHz, CDCl3): d=8.23 (distorted d, J=2.0 Hz, 1H, H-
4), 7.53–7.35 (m, 5H, aromatic), 7.34–7.27 (m, 3H, aromat-
ic), 7.26–7.19 (m, 3H, aromatic), 7.20 (distorted d, J=
8.9 Hz, 1H, H-7), 7.03 (distorted dd, J=8.9, 2.0 Hz, 1H, H-
6), 6.24 (s, 1H, CHOEt), 4.28–4.16 (m, 2H, CHOCH2CH3),
3.40 (q, J=6.9, 2H, CO2CH2CH3), 1.18 (t, J=7.3 Hz, 3H,
CHOCH2CH3), 1.14 (t, J=6.9 Hz, 3H, CO2CH2CH3);
13C NMR (75 MHz, CDCl3): d=164.6, 147.9, 137.9, 132.7,
131.1, 130.5 (br), 129.5 (br), 129.4, 128.55, 128.48, 128.33,
128.28, 125.9, 123.3, 121.3, 115.17, 106.0, 85.7, 63.9, 59.7,
14.7, 14.1; GC-MS: m/z=433 (M+, 5), 270 (3), 253 (3), 207
(3), 199 (5), 190 (9), 136 (10), 135 (100), 107 (50), 79 (53), 77
(18); anal. calcd. for C26H24ClNO3 (433.93): C 71.97, H 5.57,
N 3.23; found: C 71.90; H, 5.58, N 3.22.
1-(Methoxyphenylmethyl)-2-phenyl-6-trifluoromethylin-
dole-3-carboxylic acid methyl ester (4ja): Yield: 244.6 mg
(55% based on starting 1j; Table 2, entry 18); colorless
solid; mp 163–1668C. IR (KBr): n=1714 (s), 1548 (w), 1482
(w), 1449 (m), 1384 (m), 1320 (m), 1272 (w), 1234 (w), 1150
(m), 1094 (m), 1075 (m), 878 (w), 848 (w), 823 (m), 756 (m),
1
2-Butyl-1-(methoxyphenylmethyl)-5-phenylindole-3-car-
boxylic acid methyl ester (4ga): Yield: 267.3 mg (62% based
on starting 1g; Table 2, entry 13); colorless solid; mp 48–
498C. IR (KBr): n=2954 (m), 1697 (s), 1601 (w), 1536 (m),
1468 (m), 1409 (w), 1265 (m), 1151 (w), 1117 (m), 764 (m),
731 (m) cmÀ1; H NMR (300 MHz, CDCl3): d=8.33 (d, br,
J=8.6 Hz, 1H, H-4), 7.59–7.38 (m, 7H, aromatic), 7.35–7.27
(m, 3H, aromatic), 7.26–7.18 (m, 2H, aromatic), 6.20 (s, 1H,
CHOMe), 3.92 (s, 3H, CO2Me), 3.29 (s, 3H, CHOCH3),
2.30 (s, 3H, Me); 13C NMR (75 MHz, CDCl3): d=165.0,
149.4, 137.3, 133.3, 130.7, 130.4 (br), 129.6, 129.5 (br), 128.8,
128.7, 128.5, 125.69, 125.65 (q, J=271.7 Hz), 125.04 (q, J=
32.1 Hz), 122.3, 119.1 (q, J=3.6 Hz), 111.5 (q, J=4.5 Hz),
106.5, 87.6, 56.2, 51.1; 19F NMR (471 MHz, CDCl3): d=
À61.0 (s, 3F, CF3); GC-MS: m/z=439 (M+, 4), 303 (3), 190
(2), 122 (9), 121 (100), 105 (3), 91 (10), 77 (17); anal. calcd.
for C25H20F3NO3 (439.43): C 68.33, H 4.59, N 3.19; found: C
68.38; H, 4.60, N 3.18.
698 (m) cmÀ1 1H NMR (300 MHz, CDCl3): d=8.38–8.36
;
(m, 1H, H-4), 7.67–7.60 (m, 2H, aromatic), 7.45–7.37 (m,
2H, aromatic), 7.34–7.28 (m, 6H, aromatic), 7.25–7.20 (m,
2H, aromatic), 6.60 (s, 1H, CHOMe), 3.97 (s, 3H, CO2Me),
3.45–3.31 (m, 1H, CHHCH2CH2CH3), 3.41 (s, 3H,
CHOCH3), 3.23–3.10 (m, 1H, CHHCH2CH2CH3), 1.72–1.36
(m,
4H,
CH2CH2CH2CH3),
0.91
(t,
J=7.3 Hz,
CH2CH2CH2CH3); 13C NMR (75 MHz, CDCl3): d=166.2,
150.7, 142.3, 137.9, 135.5, 134.5, 128.7, 128.6, 127.6, 127.5,
126.5, 125.8, 122.1, 120.0, 112.8, 105.3, 86.5, 56.2, 50.9, 31.8,
25.8, 22.9, 13.7; GC-MS: m/z=427 (M+, 10), 396 (1), 264
(2), 232 (3), 204 (3), 122 (8), 121 (100), 91 (11), 77 (13);
anal. calcd. for C28H29NO3 (427.53): C 78.66, H 6.84, N 3.28;
found: C 78.46; H, 6.86, N 3.28.
1-(Methoxy-p-tolylmethyl)-2-phenylindole-3-carboxylic
acid methyl ester (4ab): Yield: 233.0 mg (60% based on
starting 1a; Table 2, entry 20); yellow solid; mp 141–1438C.
IR (KBr): n=1688 (s), 1603 (w), 1537 (m), 1480 (m), 1444
(s), 1387 (m), 1314 (w), 1250 (m), 1203 (m), 1181 (s), 1078
1
(m), 819 (m), 708 (s) cmÀ1; H NMR (300 MHz, CDCl3): d=
2-Butyl-1-(methoxyphenylmethyl)-5-methylindole-3-car-
boxylic acid methyl ester (4ha): Yield: 191.4 mg (52% based
on starting 1h; Table 2, entry 14); yellow oil. IR (film): n=
2860 (m), 2828 (w), 1697 (s), 1620 (w), 1538 (m), 1074 (m),
8.27–8.21 (m, 1H, H-4), 7.57–7.34 (m, 5H, aromatic), 7.29–
7.19 (m, 2H, aromatic), 7.16–7.03 (m, 5H, aromatic), 6.15 (s,
1H, CHOMe), 3.77 (s, 3H, CO2Me), 3.22 (s, 3H, CHOCH3),
2.30 (s, 3H, CH3C6H4); 13C NMR (75 MHz, CDCl3): d=
165.6, 147.4, 138.2, 135.0, 134.2, 131.44, 131.39, 130.3, 129.2,
128.3, 127.2, 125.8, 122.9, 122.4, 121.7, 114.2, 106.1, 87.3,
55.9, 50.9, 21.1; GC-MS: m/z=385 (M+, 6), 250 (2), 235 (5),
190 (5), 179 (4), 136 (10), 135 (100), 119 (8), 105 (5), 91 (21),
77 (2); anal. calcd. for C25H23NO3 (385.46): C 77.90, H 6.01,
N 3.63; found: C 77.98; H, 6.00, N 3.62.
1031 (w), 987 (m), 945 (w), 881 (m), 788 (m), 761 (m) cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.96–7.93 (m, 1H, H-4),
7.32–7.26 (m, 3H, aromatic), 7.23–7.16 (m, 2H, aromatic),
7.13 (d, br, J=8.1 Hz, 1H, H-7), 6.87 (distorted dd, J=8.1,
2.0 Hz, 1H, H-6), 6.55 (s, 1H, CHOMe), 3.95 (s, 3H,
CO2Me), 3.43–3.28 (m, 1H, CHHCH2CH2CH3), 3.37 (s, 3H,
3360
asc.wiley-vch.de
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 3355 – 3363

Multicomponent Cascade Reactions: A Novel and Expedient Approach to Functionalized Indoles
1-[(4-Bromophenyl)methoxymethyl]-2-phenylindole-3-car-
boxylic acid methyl ester (4ac): Yield: 281.1 mg (62% based
on starting 1a; Table 2, entry 21); yellow solid; mp 173–
1768C. IR (KBr): n=1706 (s), 1537 (w), 1482 (m), 1453 (m),
1384 (s), 1342 (w), 1257 (m), 1197 (w), 1145 (m), 1105 (w),
1078 (w), 1011 (m), 838 (m), 757 (m), 728 (m), 795 (w)
u) D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev.
2004, 248, 2365–2379.
[2] These conditions (16 atm of CO together with 5 total
atm of air, considering that the autoclave was loaded
under 1 atm of air) corresponded to 76.2% of CO in air
and were outside the explosion limits for CO in air,
which are ca. 16–70% at 18–208C and atmospheric
pressure, 14.8–71.4% at 1008C and atmospheric pres-
sure; at higher total pressure, the range of flammability
decreases: for example, at 20 atm and 208C the limits
are ca. 19 and 60%; see: C. M. Bartish, G. M. Drissel,
in: Kirk-Othmer Encyclopedia of Chemical Technology,
3rd edn., Vol. 4, (Eds.: M. Grayson, D. Eckroth, G. J.
Bushey, L. Campbell, A. Klingsberg, L. van Nes),
Wiley-Interscience, New York, 1978, p 775.
[3] a) B. Gabriele, G. Salerno, M. Costa, Top. Organomet.
Chem. 2006, 18, 239–272; b) B. Gabriele, G. Salerno,
PdI2, in: Electronic Encyclopedia of reagents for Organ-
ic Synthesis, (Ed.: D. Crich), Wiley-Interscience, 2006;
c) B. Gabriele, G. Salerno, M. Costa, Synlett 2004,
2468–2483; d) B. Gabriele, G. Salerno, M. Costa, G. P.
Chiusoli, Curr. Org. Chem. 2004, 8, 919–946; e) B. Ga-
briele, G. Salerno, M. Costa, G. P. Chiusoli, J. Organo-
met. Chem. 2003, 687, 219–228.
[4] We have reported several examples of synthesis of het-
erocycles by PdI2-catalyzed cyclization-alkoxycarbony-
lation processes. For reviews, see ref.[3] For recent ex-
amples, see: a) B. Gabriele, R. Mancuso, E. Lupinacci,
G. Salerno, L. Veltri, Tetrahedron 2010, 66, 6156–6161;
b) B. Gabriele, L. Veltri, R. Mancuso, P. Plastina, G.
Salerno, M. Costa, Tetrahedron Lett. 2010, 51, 1663–
1665; c) N. Della Cꢀ, F. Campanini, B. Gabriele, G.
Salerno, C. Massera, M. Costa, Adv. Synth. Catal. 2009,
351, 2423–2432; d) B. Gabriele, R. Mancuso, G. Sale-
rno, P. Plastina, J. Org. Chem. 2008, 73, 756–759; e) B.
Gabriele, R. Mancuso, G. Salerno, E. Lupinacci, G.
Ruffolo, M. Costa, J. Org. Chem. 2008, 73, 4971–4977;
f) B. Gabriele, R. Mancuso, G. Salerno, M. Costa, J.
Org. Chem. 2007, 72, 9278–9282; g) B. Gabriele, R.
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Fazio, L. Veltri, Adv. Synth. Catal. 2006, 348, 2202–
2222.
[5] For recent reviews on the synthesis of indoles, see:
a) C. R. Edwankar, R. V. Edwankar, O. Namjoshi, S. K.
Rallapalli, J. Yang, J. M. Cook, Curr. Opin. Drug
Discov. Devel. 2009, 12, 752–771; b) S. A. Patil, R.
Patil, D. D. Miller, Curr. Med. Chem. 2009, 16, 2531–
2565; c) O. Miyata, N. Takeda, T. Naito, Heterocycles
2009, 78, 843–871; d) B. M. Trost, M. K. Brennan, Syn-
thesis 2009, 3003–3025; e) K. Kruger, A. Tillack, M.
Beller, Adv. Synth. Catal. 2008, 350, 2153–2167; f) S.
Patil, R. Patil, Curr. Org. Synth. 2007, 4, 201–222; g) S.
Patil, J. K. Boulamwini, Curr. Org. Synth. 2006, 3, 477–
498; h) J. T. Kuethe, Chimia 2006, 60, 543–553; i) G. R.
Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875–
2911; j) S. Agarwal, S. Cammerer, S. Filali, W. Frohner,
J. Knoll, M. P. Krahl, K. R. Reddy, H. J. Knolker Curr.
Org. Chem. 2005, 9, 1601–1614; k) S. Cacchi, G. Fabri-
zi, Chem. Rev. 2005, 105, 2873–2920.
1
cmÀ1; H NMR (300 MHz, CDCl3): d=8.25–8.21 (m, 1H, H-
4), 7.56–7.32 (m, 7H, aromatic), 7.31–7.23 (m, 1H, aromat-
ic), 7.22–7.16 (m, 1H, aromatic), 7.15–7.06 (m, 3H, aromat-
ic), 6.10 (s, 1H, CHOMe), 3.78 (s, 3H, CO2Me), 3.24 (s, 3H,
CHOCH3); 13C NMR (75 MHz, CDCl3): d=165.4, 147.2,
137.1, 134.1, 131.7, 131.2, 129.3, 128.4, 127.7, 127.3, 123.2,
122.6, 121.9, 113.9, 106.6, 86.7, 56.0, 50.9; GC-MS: m/z=451
[(M+2)+, 10], 449 (M+, 10), 250 (5), 235 (10), 201 (96), 199
(100), 190 (12), 179 (9), 165 (5), 120 (9), 92 (23), 91 (22), 77
(8); anal. calcd. for C24H20BrNO3 (450.32): C 64.01, Br,
17.74, H 4.48, N 3.11; found: C 64.07; Br, 17.85, H, 4.49, N
3.10.
Acknowledgements
Financial support from the Ministero dell’Istruzione,
dell’Universitꢀ e della Ricerca (MIUR, Rome, Italy) and
from the University of Calabria (Rende, Italy) is gratefully
acknowledged (Progetto di Ricerca d’Interesse Nazionale
PRIN 2008A7P7YJ).
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ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3361

Bartolo Gabriele et al.
FULL PAPERS
lines to give methyl indole-3-carboxylates in low to
good yields (30–76%, 4 examples) was reported some
years ago: Y. Kondo, F. Shiga, N. Murata, T. Sakamoto,
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